Human serum amyloid P component (SAP) is a normal plasma protein that has been associated with amyloid fibrils in all types of amyloidosis. Amyloidosis is a disorder of protein metabolism in which normally soluble autologous proteins are deposited in tissues as abnormal insoluble fibrils that can cause structural and functional disruptions. Disorders most often associated with amyloidosis are Alzheimer's disease and maturity onset diabetes mellitus.
It has been shown that the calcium-dependent binding of SAP to amyloid fibrils in vitro protects those fibrils from proteolytic degradation by proteinases (Tennent, G. A. et al. Proc. Natl. Acad. Sci. USA. 1995, 92, 4299-4303). The participation of SAP in the pathogenesis of amyloidosis has also been confirmed in vivo (Botto, M. et al. Nature Med. 1997, 3, 855-859). It has been proposed that SAP is needed for amyloidogenesis, possibly to protect newly formed fibrils from proteolysis. If the binding of SAP to fibrils could be inhibited or reversed, the destruction of fibrils by, for example, macrophages and/or proteinases, may be allowed to proceed. Inhibition or reversal of calcium-dependent binding of SAP to amyloid fibrils (either newly synthesized or established flibrils) may therefore be used in the treatment of amyloidosis, for example in the treatment of Alzheimer's disease.
It has long been known that SAP binds to some bacterial and plant oligosaccharides in Ca2+-dependent manner. Agarose is used as a matrix for affinity column purification of SAP. Some of these oligosaccharides contain cyclic pyruvate as a common fragment and the crystal structure of a complex of SAP and its smallest ligand containing a pyruvate, methyl 4,6-(1-carboxyethylidene)-β-D-galactoside 1 (often abbreviated as MOβDG) was recently reported (J. Mol. Biol., 2002, 320, 1081-1086). It was reported that the methyl group binds to a very small lipophilic pocket and the carboxylate coordinates with both Ca2+-cations. Oxygen atoms of dioxane ring were engaged in hydrogen bonds with Asn 59 and Gln 148.

The preparation of the compound 2 has been previously reported (Carbohydrate Res. 1973, 30, 21-32) but no reference to its use as a SAP inhibitor was made.

Certain D-proline analogs of have been prepared and shown to inhibit the binding of SAP to human amyloid Aβ (1-42) fibrils and therefore may be used in the treatment or prevention of all forms of local and systemic amyloidosis (Hertel, C. et al. U.S. Pat. No. 6,103,910; Hertel, C. et al. U.S. Pat. No. 6,262,089; Pepys, M. B. et al. Nature, 2002, 417, 254-259). D-Proline mimics MOβDG and binds to the same Ca2+-dependent binding site on the SAP surface.
There remains a need for effective inhibitors of the binding of SAP to human amyloid fibrils for the use in the treatment or prevention of amyloidosis.